Molecular mechanisms driving muscle dedifferentiation during muscle lineage reprogramming
Final Report Abstract
One defining feature of all animals is the ability to move, albeit sometimes restricted to specific developmental stages. Feeding, flight, reproduction, larval migration, respiration and blood circulation, all rely on the facilitation of coordinated and directional movements that are afforded by muscles. Systemic myopathies (induced or inherited) are characterized by muscle degeneration leading to progressive weakness and in severe cases eventually to respiratory or heart failure. But not only functional impairment of muscles, also the loss of muscle lineage identity provokes severe disease conditions since it often leads to neoplastic reprogramming of muscle cells into myosarcoma, one of the four major types of cancer. In order to understand how the formation and maintenance mechanisms are impaired during muscle diseases, it is fundamental to first comprehend the naturally occurring processes. Moreover, delineating the mechanisms and factors that mediate commitment and plasticity of muscle identity will uncover molecular paradigms for regulatory strategies relevant for other lineage commitment and plasticity processes and ultimately may advance our ability to access new regenerative medicine technologies and cancer treatments. Our recent work has uncovered a naturally occurring in vivo direct lineage reprogramming process during the metamorphosis of the Drosophila musculature. It crucially depends on the T-Box transcription factor optomotor-blind-related-gene-1 (org-1), the Drosophila homolog of vertebrate TBX1, and includes dedifferentiation of somatic syncytial muscles into mononucleate myoblasts followed by redifferentiation into another type of syncytial muscle. This unusual process is reminiscent of the events that were described for muscle regeneration in newt. We further dissected the mechanisms that mediate syncytial alary muscle dedifferentiation and uncovered that the alary muscle lineage specific activity of the Drosophila Yap/TAZ homolog Yorkie (Yki), the transcriptional effector of the Hippo pathway plays a key role in initiating alary muscle dedifferentiation and fragmentation downstream of Org-1/Tup. By demonstrating that a Twist/Yki/FGFR axis plays a central role in the regulatory network that mediates syncytial muscle cell fate plasticity and initiates a lineage switch during cellular reprogramming, we identified Twist as a crucial factor that links these two mechanisms to each other. Of note, vertebrate orthologs of Twist, Yki and FGFR are well known to be involved in the reprogramming processes that transform myogenic cells into rhabdomyosarcoma. These results connect the function of this set of regulators within a naturally occurring muscle lineage reprogramming event. Apart from adding mechanistic insights into this process they are potentially also relevant for neoplastic reprogramming.
Publications
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Yorkie and JNK revert syncytial muscles into myoblasts during Org-1–dependent lineage reprogramming. Journal of Cell Biology, 218(11), 3572-3582.
Schaub, Christoph; Rose, Marcel & Frasch, Manfred
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Twist regulates Yorkie activity to guide lineage reprogramming of syncytial alary muscles. Cell Reports, 38(4), 110295.
Rose, Marcel; Domsch, Katrin; Bartle-Schultheis, Jakob; Reim, Ingolf & Schaub, Christoph
